Summary of Capabilities

Our Capabilities

The center has developed its capabilities through the hiring of faculty leaders each with ten to twenty years of experience in the pharmaceutical industry. This core team has recruited talented chemists and biologists from academia and industry to assemble a skilled and motivated team with a collaborative spirit and aggressive goals. Our expertise includes:

Assay Development

Protein expression and purification Cell-based or in vitro Multiple platforms and readouts possible

Compound Screening

Screens up to 100,000 compounds possible

Medicinal Chemistry

Internal chemists can support three to five SAR projects External chemistry FTEs support projects and tool compound synthesis

CICBDD Compound Collections

(100,000) Diversity screening compounds

Filtering: Compounds were filtered to eliminate toxic and reactive functional groups (REOS score ≥ -2,)[1] and the following physical property criteria: 200 <= MW <= 600; AlogP <= 6; #H_acc <= 10; #H_don <= 5. We intentionally allowed slight deviations from the ‘rule of five’[2] in order to permit slightly larger and more lipophilic compounds to be included since we anticipate screening some protein-protein interaction targets where these characteristics may be required for hit identification. Because this compound set was focused on maximizing Murcko scaffold diversity, all compounds were required to have at least one ring, as only such compounds have Murcko scaffolds.[3]

Murcko Scaffold Generation: Compounds were selected based on structural diversity at the Murcko scaffold level. Essentially, a compound's Murcko scaffold includes contiguous ring systems plus chains that link two or more rings. For Murcko scaffolds which contained more than 20 compounds, twenty compounds were randomly selected for that scaffold in order to maximize the diversity of scaffolds available for diversity set creation by effectively limiting the population of single scaffold-based compound sets.

Compound acquisition: Based upon the above selection process and previous experience with vendors known to be reliable for delivery and purity, a set of 100K compounds was chosen and purchased from Enamine. In addition to determination of identity and purity at the time of hit identification, 3-5% of this collection will be examined by LC/MS for identity and purity confirmation – ongoing.

(97,000) NCI Diversity Set - the CICBDD is a member of the National Cancer Institute’s Chemical Biology Consortium (CBC) (http://dctd.cancer.gov/CurrentResearch/ChemicalBioConsortium.htm). The CBC has collected a 97,000 member diversity collection that is available to augment the CICBDD diversity library for cancer related projects.

(5,000 and 10,000) Kinase targeted set –Compounds were selected from >100K compounds reviewed from Life Chemicals, ChemDiv, Asinex and Enamine kinase-focused libraries. Compounds were selected based on similarity to known kinase inhibitors as well as compounds having a hinge-binding motif (e.g. heterocycles with a high likelihood to bind the kinase hinge motif conserved in nearly every kinase-small molecule X-ray structure) and structure/ligand-based virtual screening. UNC CICBDD acquired 5K compounds that were unique when compared to the UNC 100K diversity set. 10K kinase-directed compounds were identified in the diversity set and included in the kinase set to yield 15K total kinase-directed drug-like small molecules. All compounds are stored in barcoded 384 well microplates to ensure propose compound identification. All of these compounds were rule of 5 compliant.ii

(13,392) Southern Research Library – 13,392 compounds from a collaboration with the Southern Research Institute. These compounds are the product of >20 years of internal drug discovery synthesis and have only been made available to a limited number of collaborators outside Southern Research.

(80) UNCW Natural Products – this set contains 80 unique natural products and a growing set of semi-purified fractionated isolates (3-5 compounds/fraction) obtained through a collaboration with Dr. Jeffery Wright from the University of North Carolina at Wilmington. These compounds were isolated from a unique and expanding collection of culturable marine microorganisms that include both photosynthetic microalgae and non-photosynthetic bacteria.

(40) Kinase activator library- A small library of potential allosteric kinase activators selected from a database of commercially available compounds using pharmacophore-based virtual screening. The pharmacophore model was built based on the co-crystallized allosteric PDK1 ligand.

NIH Clinical Collection - The NIH Clinical Collection and NIH Clinical Collection 2 are plated arrays of 446 and 281, respectively, small molecules that have a history of use in human clinical trials. The collection was assembled by the National Institutes of Health (NIH) through the Molecular Libraries Roadmap Initiative as part of its mission to enable the use of compound screens in biomedical research.